Ethyl homolog of vitamin b6



Patented Aug. 30, 1949 HOMOLOG OF VITAIWIN Be 7 Stanton A. Harris,Westfield, and Andrew N.'Wil- Colonia, N. .L, assignors to Merck & 00.,

Inc., Rahway, N. J a corporation of New Jersey No Drawing. Originalapplication August 27,

1942, Serial No. 456,370. :Dividedsand this anplication July 20, 1946,Serial No. 685,239

This invention relates generally to organic chemicalcompounds and tomethods of manufacturing the same; in'a more limited sense, it isconcerned with a growth-promoting factor related to pyridoxine (vitaminB6) and to procamount of piperidine, to about 24.6 g. of cyanoesses forproducing the same. acetamide dissolved in approximately 100 cc. of The.presentapplication is a division of the cohot absolute ethanol. Aftercooling, the precipipending application by the same inventors, Serial 'tated solid mass is removed and washed with No. 456,370, filed August 27,1942. "ethanol.

The present invention involves the synthesis Approximately 119 g. of theZ-ethyI- l-methof a novel organic chemical compound, 2ethyl-' oxymetliyl5-cyano-6-hydroxypyridine thus 0b- 3-hydroxy4,5-bis-(hydroxymethyl)-pyridine, a tained is suspended in aceticanhydride and material which prevents or cures an acrodyniaabout 60.?cc. of fuming nitric acid is added slowlike dermatitis in young rats andwhich possesses 1y, while the mixture is vigorously agitated andgrowth-promoting properties in the metabolism 5 maintained at atemperature of about -70 C. of plants. Upon cooling a yellow crystallinesolid appears.

The process according to the present invention The solid and liquid areslowly poured into water includes the condensation of cyanoacetamide andthe solid, which is the 3-nitro compound, with l-methoxy-ZA-hexadione(which can be obis removed, washed and dried. tained by reacting methylethyl ketone and meth- 30 About 76 g. of the 3-nitro-compound, 100 g. ofyl methoxy acetate), treatment of the 2-ethylphosphorous pentachlorideand approximately 3 methoxymethyl 5-cyano-6-hydroxypyridine 320 cc. ofdry tetrachloroethane are mixed and thus obtained with nitric acid,phosphorous heated upon an oil bath. After the reaction has halide, anda reducing agent in succession to begun, as indicated by evolution ofhydrogen produce 2-ethyl-3-amino 4 methoxymethyl-S- 25 chloride, thebath temperature is maintained at aminomethyl pyridine, diazotizationfollowed by 140-145 C. for about two hours, after which the halogenationof the product, and hydrolysis of tetrachloroethane and phosphorousoxychloride th halogen compound to yield 2-ethyl-3-hyformed are removedby distillation under reduced droxy L5 bis- (hydroxymethyl) pyridinehydropressure at below C. The residue is then dishalide. The reactionsinvolved can be repren solved in benzene and poured on crushed ice and,sented as follows: after being maintained at appromixately 0 C.

CNCH ONH- CH2OCH3 Na I ON HNOs cHaoH2ooH3+ onloom oom cmon cnu omoom o oCHsCH N OH eo Ha CHaOCHa CH20 s OzN CN P015 OzN CN B: HCLHzN CHzNHz-HCIHNO: -v p CHaCH2 N OH CH:CHz N G1 I CHaCHz N cmocm CH Br onion HOOCHzOHH3! H0 OHzBr Hi0 HO cHlon .AgCl OHaCH: CHsCHa CHaCH HBr HO] I Thefollowing example illustrates a method of carrying out the presentinvention, but it is to be understood that this example is given by wayof illustration and not of limitation.

Erample About 38.4 g. of 1-methoxy-2,4-hexadione 5 Claims. I(chasm-297.5)

(which can be obtained by condensing equimolecular proportions of methylethyl ketone and methyl methoxyacetate in the presence of sodium at alow temperature) are added with a small melting at about 191 -192 ducedin methanol, using palladium black on charcoal as a catalyst, yieldingthe dihydrochloride of 2-ethyl 3-amino--methoxymethyl-B-aminomethyl-pyridine. About 10 g. of the reduced compound are dissolvedin hot water, and approximately 6.43 g. ofwsodium nitrite and 11.3 g. ofhydrochloric acid (36%) are added. After cooling and neutralizing, themixture is concentrated under reduced pressure, extracted. with alcohol,dried and further concentrated. The product so obtained is 50 cc. ofhydrobromic acid (48%) and heated to boiling, causing evolution of.methyl bromide and hydrogen bromide. After concentration followed bycooling, crystalline 2-ethyl53-hydroxy- I then mixed with about4,5-bis-(bromomethyl) pyridine hydrobromide is obtained. About 1.04 g.of this material are dis solved in approximately 100 cc. of water andheated at about 95 C. for approximately 25 minutes, then the solution isfiltered, cooled, and shaken with about 2 g. of silver chloride. The

.solution is then filtered, concentrated almost to dryness at a lowtemperature, and diluted with acetone, yielding crystalline2-ethyl-3-hyroxy- 4.,5-bis-(hydroxymethyl) pyridine hydrochloride,

Modifications may be made in carrying out the present invention withoutdeparting from the spirit and scope thereof and the invention is to belimited only by the appended claims.

:3-hydroxy-4,5-bis- (bromomethyl) -pyridine hydrobromide with water toform 2-ethyl-3-hydroxy-4,5-bis- (hydroxymethyl) -pyridine, reacting thelatter solution with silver chloride and recovering2-ethyl-3-hydroXy-4,5-bis-(hydroxymethyD -pyridine hydrochloride.

5. The process that comprises heating 2-ethyl-3-hydroxy-4,5-bis(halomethyl)pyridine hydrohalide with water to form2-ethyl-3-hydroxy-4,5-

. bi shydroxymethyl) pyridine hydrohalide.

STANTON A. HARRIS. ANDREW N. WILSON. REFERENCES CITED The followingreferences are of record in the file of this patent:

} Enzyrnologia. VII, 28QCII) 1939, pp. 385-386.

